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Chandrani Chattopadhyay, Jason Roszik, Elizabeth Grimm; Combined inhibition of SDHA and MIF in Uveal Melanoma cells effectively reduces cell survival.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4959.
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© ARVO (1962-2015); The Authors (2016-present)
Uveal melanoma (UM) is the most frequent primary intraocular cancer in adults and about 50% of primary uveal melanoma metastasize, preferentially in liver with very poor prognosis. Poor prognosis in UM are associated with BAP1 gene alterations and loss of an entire copy of chromosome 3 (monosomy 3). Comparing monosomy 3 with non-monosomy 3 UM we revealed metabolic vulnerabilities, specifically in oxidative phosphorylation (OXPHOS), that involved an overexpression of SDHA (Succinate dehydrogenase A) in monosomy 3 cells. Our goal was to determine if SDHA can be targeted together with other over-expressed proteins in UM for an effective inhibition of cell survival.
Cell survival analyses with monosomy and disomy 3 UM cells in presence and absence of OXPHOS inhibitor, IACS-10759, developed at UT MD Anderson Cancer Center were performed. Analyses to differentiate monosomy and disomy 3 cells included seahorse analysis for OXPHOS and metabolic profile analysis with mass spectrometric methods. SDHA overexpression was knocked down using specific siRNA and MIF was blocked using ISO-1 (small molecule MIF inhibitor).
Three UM cell lines with monosomy 3 were more resistant to IACS-10759 when compared to three lines with normal chromosome 3 copy number. Further studies showed more active mitochondria and a larger mitochondrial reserve capacity in monosomy 3 cells. SDHA, a key enzyme connecting the TCA cycle to mitochondrial ETC, was found to be up regulated in monosomy 3 cells and may be responsible for the resistant phenotype as shown by rescue of sensitivity to OXPHOS inhibition post SDHA knock down. On analyzing other genes that are upregulated in monosomy 3 UM cells using Cancer Genome Atlas (TCGA) UM data we found MIF as another target. On combining SDHA inhibition (siRNA to SDHA) with MIF inhibition (ISO-1), we found this combination to be more effective than each individual treatment in blocking cell survival.
We conclude that SDHA inhibition is responsible for resistance to OXPHOS inhibition in monosomy 3 UM cells. Blocking SDHA rescues sensitivity to OXPHOS inhibition. We found that there are other targets/genes that are upregulated in monosomy 3 UM. MIF (upregulated in monosomy 3 UM) inhibition blocks cell survival and combining it with SDHA inhibition is more effective than single agent inhibitions.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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